Download Physiology Lec.(2) Dr. Abeer mansoor

Physiology
Lec.(2)
Dr. Abeer mansoor
----------------------------------------------------------Production of Red Blood Cells:Areas of the Body That Produce Red Blood Cells. In the early weeks of
embryonic life, primitive, nucleated red blood cells are produced in the yolk
sac . During the middle trimester of gestation, the liver is the main organ
for production of red blood cells, but reasonable numbers are also produced
in the spleen and lymph nodes. Then ,during the last month of gestation and
after birth ,red blood cells are in bone marrow
Pluripotential Hematopoietic Stem Cells, Growth Inducers, and
Differentiation Inducers.
The blood cells begin their lives inthe bone marrow from a single type of cell
called the pluripotential hematopoietic stem cell, from which all the cells of
the circulating blood are derived. . As these cells reproduce, a small portion
of them remains exactly like the original pluripotential cells and is retained in
the bone marrow to maintain a supply of these, although their numbers
diminish with age. Most of the reproduced cells,however, differentiate to form
the other cell types . The intermediate stage cells are very much like the
pluripotential stem cells, even though they have already become committed
to a particular line of cells and are calledcommitted stem cells.The different
committed stem cells, when grown inculture, will produce colonies of specific
types of blood cells. A committed stem cell that produces erythrocytes is
called a colony-forming unit–erythrocyte, andthe abbreviation CFU-E is used
to designate this typeof stem cell. Likewise, colony-forming units that form
granulocytes and monocytes .
Growth and reproduction of the different stemcells are controlled by multiple
proteins called growth inducers. Four major growth inducers. One of these,
interleukin-3, promotes growth and reproduction of virtually all the different
types of committed stem cells, The growth inducers promote growth but not
differentiation of the cells.This is the function of another set of proteins called
differentiation inducers .
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Regulation of Red Blood Cell Production—Role
of Erythropoietin
Tissue Oxygenation Is the Most Essential Regulator of Red
Blood Cell Production.
Any condition that causes the quantity of oxygen transported to the tissues to
decrease ordinarily increases the rate of red blood cell production. Thus,
when a person becomes extremelyanemic as a result of hemorrhage or any
other condition, the bone marrow immediately begins to producelarge
quantities of red blood cells.Also, destruction of major portions of the bone
marrow by any means, especially by x-ray therapy, causes hyperplasia of the
remaining bone marrow, thereby attempting to supplythe demand for red
blood cells in the body. At very high altitudes, where the quantity of oxygen
in the air is greatly decreased, insufficient oxygen is transported to the
tissues, and red cell production isgreatly increased. In this case, it is not the
concentration of red blood cells in the blood that controls red cell production
but the amount of oxygen transported to the tissues in relation to tissue
demand for oxygen.Various diseases of the circulation that cause decreased
blood flow through the peripheral vessels,and particularly those that cause
failure of oxygen absorption by the blood as it passes through the lungs,
can also increase the rate of red cell production. This is especially apparent in
prolonged cardiac failure and in many lung diseases, because the tissue
hypoxia resulting from these conditions increases red cell production,
with a resultant increase in hematocrit and usually total blood volume
Erythropoietin Stimulates Red Cell Production, and Its Formation
Increases in Response to Hypoxia.
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The principal stimulus for red blood cell production in low oxygen states
is a circulating hormone called erythropoietin, a glycoprotein with a molecular
weight of about 34,000. Inthe absence of erythropoietin, hypoxia has little or
no effect in stimulating red blood cell production.
Role of the Kidneys in Formation of Erythropoietin.
In the normal person, about 90 per cent of all erythropoietin is formed in the
kidneys; the remainder is formed mainly in the liver. It is not known exactly
where in the kidneys the erythropoietin is formed.
One likely possibility is that the renal tubular epithelial cells secrete the
erythropoietin, because anemic blood is unable to deliver enough oxygen
from the peritubular capillaries to the highly oxygen-consuming tubular cells,
thus stimulating erythropoietin production
Factors that decrease
oxygenation
1. Low blood volume
2. Anemia
3. Low hemoglobin
4. Poor blood flow 5. Pulmonary disease
Effect of Erythropoietin in Erythrogenesis.
the important effect of erythropoietin is to stimulate the production of
proerythroblasts from hematopoietic stem cells in the bone marrow. In
addition, once the proerythroblasts are formed, the erythropoietin causes
these cells to pass more rapidly through the different erythroblastic stages
than they normally do, further speeding up the production ofnew red blood
cells.The rapid production of cells continues .In the absence of erythropoietin,
few red blood cells are formed by the bone marrow.
. Especially important for final maturation of the red blood cells are two
vitamins, vitamin B12 and folic acid. Both of these are essential for the
synthesis of DNA, because each in a different way is required for the
formationof thymidine triphosphate, one of the essential building blocks of
DNA. Therefore, lack of either vitamin B12 or folic acid causes abnormal and
diminished DNA and, consequently, failure of nuclearmaturation and cell
division.
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Maturation Failure Caused by Poor Absorption of Vitamin
B12 from the Gastrointestinal Tract—Pernicious Anemia. A
common cause of red blood cell maturation failure is failure to absorb vitamin
B12 from the gastrointestinal tract. This often occurs in the disease pernicious
anemia, in which the basic abnormality is an atrophic gastric mucosa that fails
to produce normal gastric secretions. The parietal cells of the gastric glands
secrete a glycoprotein called intrinsic factor, which combines with vitamin B12
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in food and makes the B12 available for absorption by the gut. It does this in
the following way: (1) Intrinsic factor binds tightly withthe vitamin B12. In
this bound state, the B12 is protectedfrom digestion by the gastrointestinal
secretions. (2)
Still in the bound state, intrinsic factor binds to specific receptor sites ,
carrying intrinsic factor and the vitamin together through the membrane.
Failure of Maturation Caused by Deficiency of Folic Acid
(Pteroylglutamic Acid).
Folic acid is a normal constituentof green vegetables, some fruits, and meats
(especiallyliver). However, it is easily destroyed during cooking.Also, people
with gastrointestinal absorption abnormalities,
such as the frequently occurring small intestinal disease called sprue, often
have serious difficulty absorbing both folic acid and vitamin B12. Therefore, in
many instances of maturation failure, the cause isdeficiency of intestinal
absorption of both folic acid and vitamin B12.
Formation of Hemoglobin
Hb consists of aprotein component globin and an iron containing
Pigment haem.iron exists in ferrous form and each molecule of Hb
Contains four iron atoms .Hb combines with the oxygen to form aloose
reversible compound oxy-haemoglobin,which rapidly dissociate in the tissue
to release oxygen.
hemoglobin chain . Each chain has a molecular weight of about 16,000; four
of these in turn bind together loosely to form the whole hemoglobin molecule.
There are several slight variations in the different subunit hemoglobin chains,
depending on the amino acid composition of the polypeptide portion. The
different types of chains are designated alpha chains, beta chains, gamma
chains, and delta chains. The mostcommon form of hemoglobin in the adult
human being, hemoglobin A, is a combination of two alpha chains and two
beta chains.
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The types of hemoglobin chains in the hemoglobin
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Abnormalities of the chains can alter the physical characteristics of the
hemoglobin molecule as well. For instance, in sickle cell anemia, the amino
acid v aline is substituted for glutamic acid at one point in each of the two
beta chains. When this type of hemoglobin is exposed to low oxygen, it forms
elongated crystals inside the red blood cells that are sometimes 15
micrometers in length. These make it almost impossible for the cells to pass
through many small capillaries, and the spiked ends of the crystals are
likely to rupture the cell membranes, leading to sickle cell anemia.
Types of haemoglobin
1-foetal Hb:it is present in the fetal blood and its structure is the same as that
of adult Hb.in fetal Hbthe beta chains of globin are replaced by gamma chain
.normally fetal Hb is replaced by adult form at birth but in some cases it may
persist during adult life.The fetal Hbhas greater affinity for oxygen.
2-Methaemoglobin
When blood is exposed to various oxidizing agents or even otherwise under
the influence of certain drugs,ferrous iron is converted into ferric form.This is
known as methaemoglobin and it gives dark colour to blood.However,red cells
contain enzymes which reconvert it into haemoglobin.The absence of these
enzymes results in methaemoglobinemia
3-Carboxy haemoglobin:The affinity of carbon monoxide for haemoglobin is
greater than that of oxygen .The compound thus formed is known as
carboxyhaemoglobin.it causes areduction in oxygen transport capacity of
blood and can be fatal to life.
Iron Metabolism
Because iron is important for the formation not only of hemoglobin but also of
other essential elements inthe body (e.g., myoglobin, cytochromes,
cytochrome oxidase, peroxidase, catalase), it is important to understand
the means by which iron is utilized in the body. The total quantity of iron in
the body averages 4 to 5grams, about 65 per cent of which is in the form of
hemoglobin. About 4 per cent is in the form of myoglobin,1 per cent is in the
form of the various hemecompounds that promote intracellular oxidation, 0.1
per cent is combined with the protein transferrin in theblood plasma, and 15
to 30 per cent is stored for later use, mainly in the reticuloendothelial system
and liverparenchymal cells, principally in the form of ferritin.
Transport and Storage of Iron.
Transport, storage, and metabolism of iron in the body When iron is
absorbed from the small intestine, it immediately combines in the blood
plasma with a beta globulin, apotransferrin, to form transferrin, which is then
transported in the plasma. The iron is loosely bound in the transferrin and,
consequently, can be released to any tissue cell at any point in the body.
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Excess iron in the blood is deposited especially in the liver hepatocytes and
less in the reticuloendothelialcells of the bone marrow. In the cell cytoplasm,
iron combines mainly witha protein, apoferritin, to form ferritin. ,ferritin may
contain only a small amount of iron or a large amount. This iron stored as
ferritin is called storage iron. , ferritin particles are so small and dispersed that
they usually can be seen in the cell cytoplasm only with the electron
microscope. When the quantity of iron in the plasma falls low, some of the
iron in the ferritin storage pool is removed easily and transported in the form
of transferrin in the plasma to the areas of the body where it is needed.A
unique characteristic of the transferrin molecule is thatit binds strongly with
receptors in the cell membranes of erythroblasts in the bone marrow. Then,
along withits bound iron, it is ingested into the erythroblasts by endocytosis.
There the transferrin delivers the iron directly to the mitochondria, where
heme is synthesized. In people who do not have adequate quantitiesof
transferrin in their blood, failure to transport iron to the erythroblasts in this
manner can cause severehypochromic anemia
Destruction of Hemoglobin.
When red blood cells burst and release their hemoglobin, the hemoglobin is
phagocytized almost immediately by macrophages in many parts of the body,
but especially by the Kupffer cells of the liver and macrophages of the spleen
and bone marrow. During the next few hours to days, the macrophages
release iron from the hemoglobin and pass it back into the blood, to be
carried by transferring either to the bone marrow for the production ofnew
red blood cells or to the liver and other tissues for storage in the form of
ferritin. The porphyrin portionof the hemoglobin molecule is converted by the
macrophages, through a series of stages, into the bile pigment bilirubin,
which is released into the blood and later removed from the body by secretion
through theliver into the bile;
Anemias
Anemia means deficiency of hemoglobin in the blood, which can be caused by
either too few red blood cellsor too little hemoglobin in the cells. Some types
of anemia and their physiologic causes are the following.
Blood Loss Anemia.
After rapid hemorrhage, the body replaces the fluid portion of the plasma in
1 to 3 days,but this leaves a low concentration of red blood cells. If a second
hemorrhage does not occur, the red bloodcell concentration usually returns to
normal within 3 to 6 weeks.In chronic blood loss, a person frequently cannot
absorb enough iron from the intestines to form hemoglobinas rapidly as it is
lost. Red cells are then produced that are much smaller than normal and have
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toolittle hemoglobin inside them, giving rise to microcytic, hypochromic
anemia, .
Aplastic Anemia. Bone marrow aplasia means lack of functioning bone
marrow. For instance, a person exposed to gamma ray radiation from a
nuclear bomb can sustain complete destruction of bonemarrow, followed in a
few weeks by lethal anemia. Likewise, excessive x-ray treatment, certain
industrial chemicals, and even drugs to which the person might be sensitive
can cause the same effect.
Megaloblastic Anemia. Based on the earlier discussions of vitamin B12,
folic acid, and intrinsic factor from the stomach mucosa, one can readily
understand that loss of any one of these can lead to slow reproduction
oferythroblasts in the bone marrow. As a result, the red cells grow too large,
with odd shapes, and are called
megaloblasts. Thus, atrophy of the stomach mucosa, as occurs in pernicious
anemia, or loss of the entire stomach after surgical total gastrectomy can lead
to megaloblastic anemia. Also, patients who have intestinal sprue, in which
folic acid, vitamin B12, and other vitamin B compounds are poorly absorbed,
oftendevelop megaloblastic anemia. .
Hemolytic Anemia. Different abnormalities of the red blood cells, many of
which are hereditarily acquired,make the cells fragile, so that they rupture
easily as they go through the capillaries, especially through the spleen. Even
though the number of red blood cells formed may be normal, or even much
greater than normal in some hemolytic diseases, the life span of the fragile
red cell is so short that the cells are destroyed faster than they can be
formed, and serious anemia results. Some of these types of anemia are
thefollowing.
In hereditary spherocytosis, the red cells are verysmall and spherical
In sickle cell anemia, which is present in West African and American blacks,
the cellshave an abnormal type of hemoglobin called hemoglobin S,
containing faulty beta chains in the hemoglobinmolecule, When this
hemoglobin is exposed to low concentrations of oxygen, it precipitates into
long crystals inside the red blood cell.These crystals elongate the cell and give
it the appearance of a sickle rather than a biconcave disc. The precipitated
hemoglobin also damages the cell membrane, so that the cells become
highlyfragile, leading to serious anemia.
In erythroblastosis fetalis, Rh-positive red blood cells in the fetus are attacked
by antibodies from an Rh-negative mother. These antibodies make the Rhpositive cells fragile, leading to rapid rupture andcausing the child to be born
with serious anemia
Polycythemia
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Secondary Polycythemia. Whenever the tissues become hypoxic because
of too little oxygen in the breathe air, such as at high altitudes, or because of
failure of oxygen delivery to the tissues, such as in cardiacfailure, the bloodforming organs automatically produce large quantities of extra red blood cells.
Thiscondition is called secondary polycythemia, and the red cell count
commonly rises to 6 to 7 million/mm3,about 30 per cent above normal.A
common type of secondary polycythemia, called physiologic polycythemia,
occurs in natives who live at altitudes of 14,000 to 17,000 feet, where the
atmospheric oxygen is very low.The blood count is generally 6 to7million
permm3
Polycythemia Vera (Erythremia).
a pathological condition known as polycythemia vera, in which the red blood
cell count may be 7 to 8million/mm3 and the hematocrit may be 60 to 70 per
cent instead of the normal 40 to 45 per cent. Polycythemiavera is caused by a
genetic aberration in the hemocytoblastic cells that produce the blood cells.
In polycythemia vera, not only does the hematocrit increase, but the total
blood volume also increases, onsome occasions to almost twice normal.As a
result, the entire vascular system becomes intensely engorged. Inaddition,
many blood capillaries become plugged by the viscous blood; the viscosity of
the blood in polycythemia vera increase
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